Throughout this application, various publications are referenced by Arabic numerals. Full citations for these publications may be found listed at the end of the specification immediately preceding the Sequence Listing. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein.
The product of the Schizosaccharomyces pombe rad9 gene is required for cell cycle arrest at the G2 checkpoint in response to incompletely replicated or damaged DNA. Cell cycle checkpoints are regulatory mechanisms that prevent cell cycle progression in the presence of DNA damage or incompletely replicated DNA (1-4). In the fission yeast S. pombe, loss of any of the rad1, rad3, rad9, rad17, or hus1 genes abolished the G2 checkpoint delays which usually follow exposure to DNA damaging or replication blocking agents (3-5). This result suggests that these five genes regulate a single common pathway linking aberrant DNA structures to cell cycle control. Evidence for the conservation of checkpoint control pathways at the molecular level is suggested by the similarity of the gene product of the human ATM (Ataxia telangiectasia mutated) locus and the proteins encoded by the checkpoint genes rad3 from S. pombe and MEC1 from S. cerevisiae (6). It is likely that the ATM gene product is involved in checkpoint control in human cells, as cell lines derived from AT patients exhibit a number of defects indicative of checkpoint deficiency, including sensitivity to ionizing radiation (8), and an increased rate of spontaneous mutation (8). However, the primary defect in AT seems to be at the G1-S rather than at the G2-M checkpoint (9, 10).